Cumulative exposure characteristics of vegetable farmers exposed to Chlorpyrifos in Central Java - Indonesia; a cross-sectional study.

BACKGROUND: Agriculture is a major economic sector in Indonesia. Chemical pesticides are widely being used in agriculture for controlling pest. There is a growing concern that pesticide exposure, particularly chlorpyrifos (CPF) exposure, combined with other occupational characteristics that determine the level of exposure, can lead to further health impacts for farmers. Our objective was to evaluate the cumulative exposure characteristics among farmers exposed to CPF by using a validated algorithm. METHODS: We conducted a cross-sectional study of 152 vegetable farmers aged 18-65 who actively used CPF for at least 1 year in Central Java, Indonesia. Subject characteristics were obtained using a structured interviewer-administered questionnaire, addressed for sociodemographic and work-related characteristics. The cumulative exposure level (CEL) was estimated as a function of the intensity level of pesticide exposure (IL), lifetime years of pesticide use and the number of days spraying per year. CEL was subsequently classified into two groups, high and low exposure groups. The difference in characteristics of the study population was measured using Chi-square, independent-t or Mann-Whitney test. Association between CEL and its characteristics variables were performed by multiple linear regression. RESULTS: Seventy-one subjects (46.7%) were classified as the high exposure group. The use of multiple pesticide mixtures was common among our study population, with 94% of them using 2 or more pesticides. 73% reported direct contact with concentrated pesticides product, and over 80% reported being splashed or spilt during preparation or spraying activity. However, we found that the proportion of proper personal protective equipment (PPE) use in our subjects was low. Higher volume of mixture applied (p <  0.001) and broader acres of land (p = 0.001) were associated with higher cumulative exposure level, while using long-sleeved clothes and long pants (p <  0.05) during pesticide spraying were associated with lower cumulative exposure after adjusted for age and gender. CONCLUSIONS: These findings indicate an inadequate knowledge of using pesticides properly. Thus, we recommend comprehensive training on pesticide usage and encourage proper PPE to reduce the exposure level.

Wound Healing in Diabetic Foot Ulcer Patients Using Combined Use of Platelet Rich Fibrin and Hyaluronic Acid, Platelet Rich Fibrin and Placebo: An Open Label, Randomized Controlled Trial.

BACKGROUND: Autologous platelet-rich fibrin (A-PRF) is an adjunctive method for diabetic foot ulcer (DFU) in addition to glycaemic control and debridement. This study aimed to evaluate the role of A-PRF + hyaluronic acid (HA), A-PRF and sodium chloride 0.9% (control) in DFU wound healing. Nowaday, the use of  PRF autologous consider as adjuvant therapy in DFU treatment. METHODS: This open-label randomized controlled trial was conducted at Koja District Hospital and Gatot Soebroto Hospital from July 2019 to April 2020. DFU patients with wound duration of three months, Wagner-2, and ulcer size < 40 cm2 were recruited and randomly assigned into A-PRF + AH, A-PRF and control group. On day-0, day-3 and day -7, samples and photographs were taken. Samples were analysed with ELISA and photographs were analysed with ImageJ to calculate granulation index (GI). Statistical analysis was performed using SPSS version 20. RESULTS: Topical therapy with A-PRF + AH was associated with a significant increase in VEGF from day 0 (232.8 pg/mg) vs day 7 (544.5 pg/mg) compared to A-PRF on day 0 (185.7 pg/mg) vs day 7 (272.8 pg/mg), and the controls on day 0 (183.7 pg/mg) vs day 7 (167.4 pg/mg). On evaluation  of VEGF swab, there is increasing significantly in A-PRF+HA group compare others group in day -3 ( p=0.022) and day -7 (p= 0.001).In the A-PRF + AH group, there was a significant decrease in IL-6 from day 0 (106.4 pg/mg) vs day 7 (88.7 pg/mg) compared with PRF on day 0 (91.9 pg/mg) vs day 7 (48,8 pg/mg). IL-6 was increased in the control group from day 0 (125.3 pg/mg) vs day 7 (167.9 pg/mg). On evaluation  of IL-6 swab, there is decreasing significantly in A-PRF+HA group compare others group in day -7 (p= 0.041). CONCLUSION: The PRF + HA combination increased angiogenesis and reduced inflammation in DFUs and may represent a new DFU therapy.

The determinants of thyroid function among vegetable farmers with primary exposure to chlorpyrifos: A cross-sectional study in Central Java, Indonesia.

Objectives: Occupational pesticide exposure, chlorpyrifos (CPF) in particular, may adversely affect the thyroid. The purpose of this study was to evaluate the determinants of thyroid function as indicated by the serum concentration of thyroid-stimulating hormone (TSH) among Indonesian vegetable farmers with primary exposure to CPF. Methods: A total of 151 vegetable farmers participated in this study. The sociodemographic and occupational characteristics of the participants were obtained using a structured interviewer-administered questionnaire. A validated quantitative method was used to estimate the cumulative exposure level (CEL). Serum TSH, thyroglobulin (Tg), free thyroxine (FT4), and urinary iodine excretion (UIE) were measured in the laboratory. The difference in TSH concentrations according to CEL and other characteristics were analysed using the Mann-Whitney U test. A multiple linear regression model was used to evaluate the potential determinants of TSH. Results: The mean age was 50 (SD 9.4) years. The median concentrations of TSH, FT4, and Tg/FT4 ratio were 1.46 mIU/L, 1.17 ng/dL, and 6.23 × 102, respectively. We observed that higher TSH concentrations were found among those with a higher Tg/FT4 ratio, were classified as high CEL, and had lower UIE or FT4. Conclusions: Our findings show that Tg/FT4 ratio, CEL, FT4, UIE concentrations, and post-spraying days were determinants of TSH concentrations among farmers with primary exposure to CPF. These results indicate that farmers are exposed to agents with thyroid-disrupting properties, thus supporting previous evidence showing the potential for thyroid disorders in agricultural populations exposed to pesticides.

The Role of CYP2B6*6 Gene Polymorphisms in 3,5,6-Trichloro-2-pyridinol Levels as a Biomarker of Chlorpyrifos Toxicity Among Indonesian Farmers.

OBJECTIVES: One of the most widely used pesticides today is chlorpyrifos (CPF). Cytochrome P450 (CYP)2B6, the most prominent catalyst in CPF bioactivation, is highly polymorphic. The objective of our study was to evaluate the role of CYP2B6*6, which contains both 516G>T and 785A>G polymorphisms, in CPF toxicity, as represented by the concentration of 3,5,6-trichloro-2-pyridinol (TCPy), among vegetable farmers in Central Java, Indonesia, where CPF has been commonly used. METHODS: A cross-sectional study was conducted among 132 vegetable farmers. Individual socio-demographic and occupational characteristics, as determinants of TCPy levels, were obtained using a structured interviewer-administered questionnaire and subsequently used to estimate the cumulative exposure level (CEL). TCPy levels were detected with liquid chromatography-mass spectrometry. CYP2B6*6 gene polymorphisms were analyzed using a TaqMan® SNP Genotyping Assay and Sanger sequencing. Linear regression analysis was performed to analyze the association between TCPy, as a biomarker of CPF exposure, and its determinants. RESULTS: The prevalence of CYP2B6*6 polymorphisms was 31% for *1/*1, 51% for *1/*6, and 18% for *6/*6. TCPy concentrations were higher among participants with CYP2B6*1/*1 than among those with *1/*6 or *6/*6 genotypes. CYP2B6*6 gene polymorphisms, smoking, CEL, body mass index, and spraying time were retained in the final linear regression model as determinants of TCPy. CONCLUSIONS: The results suggest that CYP2B6*6 gene polymorphisms may play an important role in influencing susceptibility to CPF exposure. CYP2B6*6 gene polymorphisms together with CEL, smoking habits, body mass index, and spraying time were the determinants of urinary TCPy concentrations, as a biomarker of CPF toxicity.

Oral Ferrous Sulphate Improves Functional Capacity on Heart Failure Patients with Iron Deficiency Anemia.

Background: Iron deficiency anemia (IDA) in heart failure (HF) is associated with poor functional capacity. Several studies reported the benefit of iron therapy in HF with IDA on improving functional capacity. Therefore, we attempt to investigate the effect of oral iron supplementation on functional capacity in HF patients with IDA. Results: A double blind randomized controlled trial was conducted in National Cardiovascular Center Harapan Kita Hospital Universitas Indonesia. A total of 54 HFREF patients with IDA were enrolled and randomized to either oral Ferrous Sulphate (FS) 200 mg three times a day or placebo with 1:1 ratio for 12 weeks. Primary outcome was functional capacity measured by a six-minute walk test. There were 41 participants completed the study (FS n = 22, placebo n = 19). Ferrous sulphate significantly improved functional capacity changes (46.23 ± 35 m vs -13.7 ± 46 m, p < 0.001, CI -86.8 to -33.2) compared with placebo groups respectively after 12 weeks intervention. Conclusions: Oral FS supplementation for 12 weeks significantly improved functional capacity in HF patients with IDA. Trial registration: clinicaltrials.gov, NCT02998697. Registered 14 December 2016 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02998697.

The role of VEGF, PDGF and IL-6 on diabetic foot ulcer after Platelet Rich Fibrin + hyaluronic therapy.

BACKGROUND: Current standard management of diabetic foot ulcers (DFUs) consists of surgical debridement followed by soak NaCl 0.9% gauzes tight infection and glycaemic control. Nowadays the use of advanced platelet-rich fibrin (A-PRF) has emerged as an adjunctive method for treating DFUs. This study was conducted to demonstrate the ability of combine A-PRF + HA as a complementary therapy in DFUs healing related with angiogenesis,inflammation and granulation index process. METHODS: This open label randomized controlled trial was conducted in Koja District Hospital and Gatot Soebroto Hospital Jakarta, Indonesia on July 2019-April 2020. DFUs patients with wound duration of three months, Wagner-2, with size of ulcer less than 40 cm2 were included in the study. The number of subjects was calculated based on the rule of thumb and allocated randomly into three groups, namely topical A-PRF + HA, A-PRF and Sodium Chloride 0.9% as a control, for each of 10 subjects. A-PRF made by 10 mL venous blood, centrifuge 200 G in 10 min, meanwhile A-PRF + HA though mix both them with vertex machine around 5 min. Biomarker such as VEGF, PDGF and IL-6 examined from DFU taken by cotton swab and analysis using ELISA. Granulation Index was measured using ImageJ. Biomarkers and granulation index were evaluated on day 0, 3, 7 and 14. Data were analysed using SPSS version 20 with Anova and Kruskal Wallis test to compare the angiogenesis and inflammation effect between the three groups. RESULT: In topical dressing A-PRF + HA, there is an increase in delta VEGF on day-3 (43.1 pg/mg protein) and day-7 (275,8 pg/mg protein) compared to A-PRF on day-3 (1.8 pg/mg protein) and day-7 (104.7 pg/mg protein), also NaCl (control) on day-3 (-4.9 pg/mg protein) and day-7 (28.3 pg/mg protein). So that the delta VEGF of A-PRF + HA group increase significantly compared with others on day-3 (p = 0.003) and day- 7 (p < 0.001). Meanwhile A-PRF + AH group, there is also a decrease in delta IL-6 after therapy on day-3 (-10.9 pg/mg protein) and day-7 (-18.3 pg/mg protein) compared to A-PRF in delta IL-6 on day- 3 (-3.7 pg/mg protein) and on day-7 (-7.8 pg/mg protein). In NaCl (control) group there is a increase delta IL-6 on day-3 (4.3 pg/mg protein) and on day-7 (35.5 pg/mg protein). So that the delta IL-6 of A-PRF + HA group decrease significantly compared with others only on day- 7 (p = 0.015). In PDGF le level analysis, A-PRF + HA group increase significantly (p = 0.012) only in day -7 compare with other group (5.5 pg/mg protein). CONCLUSION: The study shows the superior role of combined A-PRF + HA in the treatment DFU though increase angiogenesis and decrease inflammation pathway. The advantage of using A-PRF + HA is that it accelerates wound healing by increasing granulation tissue compared to A-PRF alone.

Structural and morphological changes in rat ventricular myocardium induced by chronic systemic hypoxi.

AIM: to explore the effects of chronic systemic hypoxia on myocardial structure and morphology. In addition, the goal of present study is to develop a hypoxia-induced heart failure model in rats. METHODS: Sprague-Dawley male rats, weighing 220-250 g at the time of recruitment were randomly allocated into 7 groups (n = 4 per group), the control normoxia group was exposed to room air, while the hypoxia groups were caged in a plexiglas hypoxic chamber (8% O2 and 92% N2) for 28 days. Structural and morphological changes of ventricular myocardium were determined at day 28, while blood gas parameters were measured at day 1, 3, 7, 14, 21, and 28. RESULTS: histopathologic and morphologic evaluation showed massive hypertrophy accompanied by damage of the intercalated disk (ID) structure, angiogenesis, necrosis, fibrosis, and apoptosis as a hallmark of ventricular remodeling. At the end of treatment, there were increases of LV (2.79 vs 3.71) and RV (1.72 vs 2.54) wall thicknesses, and also in hypertrophy index (from 3.19 to 5.74). Blood gas analysis revealed metabolic acidosis compensated by respiratory alkalosis. There was an observed decrease of blood gas parameters in hypoxia group compared to control group: PO2 (24.7 vs 96.4 mm Hg), PCO2 (18.2 vs 40.4 mm Hg), O2 saturation (25.5 vs 94.1 %), and HCO3 (10.1 vs 23.4 mmol/L). On the other hand an increase in hemoglobin level (221.5 vs 120.3 g/L), haematocrit level (68.6 vs 45.2 %), and red blood cell count (10.4 vs 6.9 µL/1000) could be observed. CONCLUSION: our data clearly show that chronic systemic hypoxia causes massive ventricular hypertrophy accompanied by severe structural and morphological impairment of ventricular myocardium, which eventually results in cardiac failure.

Biocurcumin as Radiosensitiser for Cervical Cancer Study (BRACES): A Double-Blind Randomised Placebo-Controlled Trial.

Cervical cancer is a leading cause of death among women worldwide, particularly in Indonesia. The main treatment of advanced-stage cervical cancer is radiation; however, the outcomes do not meet the required expectations. [1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5dione] has been reported in several studies for its potency in cancer therapy. This study aims to investigate the clinical and molecular [(malondialdehyde (MDA) and NF-κB levels] effects, apoptotic index, and safety of Biocurcumin (BCM-95) as a radiosensitiser in cervical cancer. In this double-blind placebo randomised-controlled trial, we randomised 121 patients into 2 groups (BCM-95 or placebo). MDA and their NF-κB levels and apoptotic index were measured before and after administering 24 Gy of radiation. MDA was identified using Wills' method, whereas NF-κB was identified via ELISA. The apoptotic index was identified using TUNEL and DAPI staining. The clinical response was classified based on the RECIST. MDA levels before radiation were similar between both groups in per protocol and intention-to-treat (ITT) analyses (p = 0.53 and p = 0.16, respectively). After radiation, MDA levels increased in both groups with no significant differences in per protocol and ITT analyses (p = 0.52 and p = 0.18, respectively). NF-κB levels before radiation were similar between the two groups in per protocol and ITT analyses (p = 0.92 and p = 0.98, respectively). After radiation, the BCM-95 group showed an increase in the NF-κB levels compared with the placebo group in per protocol analysis but not in ITT analysis (p = 0.018 and p = 0.42, respectively). The BCM-95 group had a higher apoptotic index before radiation in per protocol analysis but not in ITT analysis (p = 0.01 and p = 0.61, respectively). After radiation, the apoptotic index remained higher in the BCM-95 group in per protocol analysis but not in ITT analysis (p = 0.04 and p = 0.91, respectively). There was no significant difference in complete response between the groups (per protocol, p = 0.61; ITT analysis, p = 0.90). Although BCM-95 can regulate ROS, NF-κB, and apoptosis in human cervical cancer, it is not significant. Therefore, BCM-95 does not improve clinical response to radiation treatment.

Effects of α-tocopherol on hemolysis and oxidative stress markers on red blood cells in ß-thalassemia major.

BACKGROUND: The accumulation of unpaired α-globin chains in patients with ß-thalassemia major may clinically create ineffective erythropoiesis, hemolysis, and chronic anemia. Multiple blood transfusions and iron overload cause cellular oxidative damage. However, α-tocopherol, an antioxidant, is a potent scavenger of lipid radicals in the membranes of red blood cells (RBCs) of patients with ß-thalassemia major. PURPOSE: To evaluate the effects of α-tocopherol on hemolysis and oxidative stress markers on the RBC membranes of patients with ß-thalassemia major. METHODS: Forty subjects included in this randomized controlled trial were allocated to the placebo and α-tocopherol groups. Doses of α-tocopherol were based on Institute of Medicine recommendations: 4-8 years old, 200 mg/day; 9-13 years old, 400 mg/day; 14-18 years old, 600 mg/day. Hemolysis, oxidative stress, and antioxidant variables were evaluated before and after 4-week α-tocopherol or placebo treatment, performed before blood transfusions. RESULTS: Significant enhancements in plasma haptoglobin were noted in the α-tocopherol group (3.01 mg/dL; range, 0.60-42.42 mg/dL; P=0.021). However, there was no significant intergroup difference in osmotic fragility test results; hemopexin, malondialdehyde, reduced glutathione (GSH), or oxidized glutathione (GSSG) levels; or GSH/GSSG ratio. CONCLUSION: Use of α-tocopherol could indirectly improve hemolysis and haptoglobin levels. However, it played no significant role in oxidative stress or as an endogen antioxidant marker in ß-thalassemia major.

Expression of B-type natriuretic peptide-45 (BNP-45) gene in the ventricular myocardial induced by systemic chronic hypoxia.

AIM: To investigate the expression of B-type natriuretic peptide-45 (BNP-45) gene which was induced by systemic chronic hypoxia, and whether these changes would be different from BNP-45 protein in the plasma and its mRNA in the ventricular myocardial. This study also aimed to test the hypothesis that systemic chronic hypoxia may cause heart failure. METHODS: Although clinical use of BNP as a biomarker in heart failure is increasing, the specificity of BNP for heart failure is not robust, suggesting that other mechanisms beyond simple ventricular stretch stimulate BNP release. Plasma BNP levels were markedly increased in patients with coronary artery disease but without concomitant left ventricular dysfunction. Thus, elevated BNP levels do not necessarily reflect heart failure but may also result from cardiac ischemia. Sprague-Dawley male rats, weighing 220-250 g at the time of recruitment were randomly divided into 7 groups (n = 4 per group), the control normoxia group was exposed to room air, while the hypoxia group were caged in a plexiglass hypoxic chamber (8%O2 and 92% N2) for 1, 3, 7, 14, 21, and 28 days, respectively. RESULTS: Our data clearly showed that plasma BNP-45 and ventricular BNP-45 mRNA concentration were markedly increased which reached its peak on day 21 after treatment. CONCLUSION: Regulation of BNP-45 gene expression occurred at transcription as well as post-transcription level. Systemic chronic hypoxia could result in heart failure, especially when the hypoxia is severe and prolonged.

Neuroglobin correlates with cryptochrome-1 in obstructive sleep apnea with primary aldosteronism.

BACKGROUND: Neuroglobin (Ngb) is highly expressed in the suprachiasmatic nucleus, and can regulate Per1 gene expression. It is still not known whether Ngb also influences Cryptochrome (Cry). Cry is implicated in hypertension and primary aldosteronism (PA) in mice. There is a strong correlation between Obstructive Sleep Apnea (OSA) and PA. We propose to prove that Ngb and Cry play a role in OSA with PA. METHODS: Subjects were recruited consecutively from residents of Jakarta, Indonesia; subjects aged 30-65 years with moderate to severe OSA and hypertension were included in the study. OSA was diagnosed using an unattended type 2 portable monitor (Alice Pdx), hypertension was diagnosed when morning blood pressure exceeded 140/90 mmHg or when taking anti-hypertensive drugs. Serum concentration of aldosterone, renin, Cry1, Cry2 and Ngb protein were determined using ELISA method. Primary aldosteronism (PA) was defined as ARR ≥20. RESULTS: Forty subjects were recruited, 26 male and 14 female, median age 52.5 years, BMI 27.46 kg/m2, and AHI 34.8 times/hour. We found 16 subjects with PA and 24 non PA. Cry1 and Cry2 did not correlate with ARR in PA and non PA groups. Ngb correlated positively with Cry1 (Spearman's rho = 0.455, p = 0.038) but not Cry2 in PA patients. Cry1 concentration decreased in severe hypoxia. CONCLUSIONS: Ngb correlates with Cry1 in OSA with PA. There is no correlation between Cry1 or Cry2 with PA.

Anti-Diabetic Potential of Murraya Koenigii (L.) and its Antioxidant Capacity in Nicotinamide-Streptozotocin Induced Diabetic Rats.

AIM AND OBJECTIVE: The present study aims to investigate whether the antihyperglycemic effect of Murraya koenigii is mediated by antioxidant properties and insulin mimetic effect. METHODS: Thirty Spraque-Dawley rats were induced hyperglycemia by streptozotocin and nicotinamide (STZ-NA). The STZ-NA diabetic rats were treated with an ethanolic extract of Murraya koenigii 200 mg/kg b.w and 400 mg/kg b.w. One group was treated with glibenclamide (1 mg/kg b.w). After the administration of Murraya koenigii extract and glibenclamide for four weeks, the rats were sacrificed. Blood and organ samples were collected under a fasting condition. The body weight and blood glucose levels were measured. Hepatic enzymes were determined using a commercial kit, protein levels were estimated by Bradford's method, and plasma insulin was assayed by an ELISA kit. Malondialdehyde (MDA) and reduced glutathione (GSH) levels were estimated by the TBA-Wills method and Ellman's method, respectively. RESULTS: Ethanolic extract of Murraya koenigii showed a significant reduction in blood glucose level at both doses, 200 and 400 mg/kg b.w. In addition, Murraya koenigii exhibited a profound antioxidant effect with decreased MDA level and increased GSH level, particularly at the 200 mg/kg b.w. and significantly decreased the HOMA-IR index. CONCLUSIONS: The present study reveals that Murraya koenigii possesses antidiabetic activity and antioxidant effects on STZ-NA induced diabetes mellitus.

Effect of Apium graveolens Extract Administration on the Pharmacokinetics of Captopril in the Plasma of Rats.

Apium graveolens (celery) is an edible and traditionally medicinal plant that is used worldwide, among others for the treatment of hypertension. Combining celery with antihypertensive drugs can affect the pharmacodynamics and pharmacokinetics of the latter drugs. The aim of the study is to assess the effects of administrating the celery extract on captopril pharmacokinetics. Sprague-Dawley strain rats were divided into two groups (n = 6). Group I was given captopril (10 mg/kg Body Weight (BW)) orally, while Group II was pretreated with celery extract orally (40 mg/kg BW) an hour before administration of captopril. The blood samples were withdrawn at various intervals after drug administration. The captopril concentration was determined using liquid chromatography-mass spectrometry (LC-MS/MS) and from the blood data, the values of Ke, Cmax, Tmax, T1/2, and area under the curve (AUC) were calculated. The results showed that oral administration of the celery extract increased Cmax (38.67%), T1/2 (37.84%), and AUC (58.10%) and decreased Ke (27.45%) of captopril in Group II (celery + captopril) compared with Group I (captopril). In conclusion, celery extract can alter the pharmacokinetic of captopril when given in combination. The combination might be beneficial for the treatment of hypertension, as celery causes an increase in the plasma level of captopril, which can enhance its efficacy.

Association of the HLA-B alleles with carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis in the Javanese and Sundanese population of Indonesia: the important role of the HLA-B75 serotype.

Carbamazepine (CBZ) is a common cause of life-threatening cutaneous adverse drug reactions such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Previous studies have reported a strong association between the HLA genotype and CBZ-induced SJS/TEN. We investigated the association between the HLA genotype and CBZ-induced SJS/TEN in Javanese and Sundanese patients in Indonesia. Nine unrelated patients with CBZ-induced SJS/TEN and 236 healthy Javanese and Sundanese controls were genotyped for HLA-B and their allele frequencies were compared. The HLA-B*15:02 allele was found in 66.7% of the patients with CBZ-induced SJS/TEN, but only in 29.4% of tolerant control (p = 0.029; odds ratio [OR]: 6.5; 95% CI: 1.2-33.57) and 22.9% of healthy controls (p = 0.0021; OR: 6.78; 95% CI: 1.96-23.38). These findings support the involvement of HLA-B*15:02 in CBZ-induced SJS/TEN reported in other Asian populations. Interestingly, we also observed the presence of the HLA-B*15:21 allele. HLA-B*15:02 and HLA-B*15:21 are members of the HLA-B75 serotype, for which a greater frequency was observed in CBZ-induced SJS/TEN (vs tolerant control [p = 0.0078; OR: 12; 95% CI: 1.90-75.72] and vs normal control [p = 0.0018; OR: 8.56; 95% CI: 1.83-40]). Our findings suggest that screening for the HLA-B75 serotype can predict the risk of CBZ-induced SJS/TEN more accurately than screening for a specific allele.